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01-12-2020 | Phenylketonuria | Study protocol

Impact of phenylalanine on cognitive, cerebral, and neurometabolic parameters in adult patients with phenylketonuria (the PICO study): a randomized, placebo-controlled, crossover, noninferiority trial

Authors: Roman Trepp, Raphaela Muri, Stephanie Abgottspon, Lenka Bosanska, Michel Hochuli, Johannes Slotboom, Christian Rummel, Roland Kreis, Regula Everts

Published in: Trials | Issue 1/2020

Abstract

Background

The population of adult patients with early-treated phenylketonuria (PKU) following newborn screening is growing substantially. The ideal target range of blood phenylalanine (Phe) levels in adults outside pregnancy is a matter of debate. Therefore, prospective intervention studies are needed to evaluate the effects of an elevated Phe concentration on cognition and structural, functional, and neurometabolic parameters of the brain.

Methods

The PICO (Phenylalanine and Its Impact on Cognition) Study evaluates the effect of a 4-week Phe load on cognition and cerebral parameters in adults with early-treated PKU in a double-blind, randomized, placebo-controlled, crossover, noninferiority trial.

Participants

Thirty adult patients with early-treated PKU and 30 healthy controls comparable to patients with regard to age, sex, and educational level will be recruited from the University Hospitals Bern and Zurich, Switzerland. Patients are eligible for the study if they are 18 years of age or older and had PKU diagnosed after a positive newborn screening and were treated with a Phe-restricted diet starting within the first 30 days of life.

Intervention: The cross-over intervention consists of 4-week oral Phe or placebo administration in patients with PKU. The study design mimics a Phe-restricted and a Phe-unrestricted diet using a double-blinded, placebo-controlled approach.

Objectives

The primary objective of the PICO Study is to prospectively assess whether a temporarily elevated Phe level influences cognitive performance (working memory assessed with a n-back task) in adults with early-treated PKU. As a secondary objective, the PICO Study will elucidate the cerebral (fMRI, neural activation during a n-back task; rsfMRI, functional connectivity at rest; DTI, white matter integrity; and ASL, cerebral blood flow) and neurometabolic mechanisms (cerebral Phe level) that accompany changes in Phe concentration. Cognition, and structural and functional parameters of the brain of adult patients with early-treated PKU will be cross-sectionally compared to healthy controls. All assessments will take place at the University Hospital Bern, Switzerland.

Randomization

Central randomization will be used to assign participants to the different treatment arms with age, sex, and center serving as the stratification factors. Randomization lists will be generated by an independent statistician.

Blinding: All trial personnel other than the statistician generating the randomization list and the personnel at the facility preparing the interventional product are blinded to the assigned treatment.

Discussion

Using a combination of neuropsychological and neuroimaging data, the PICO Study will considerably contribute to improve the currently insufficient level of evidence on how adult patients with early-treated PKU should be managed.

Trial registration

The study is registered at clinicaltrials.gov (NCT03788343) on the 27th of December 2018, at kofam.ch (SNCTP000003117) on the 17th of December 2018, and on the International Clinical Trials Registry Platform of the WHO.

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Blau N, Van Spronsen FJ, Levy HL. Phenylketonuria. Lancet. 2010;376(9750):1417–27.PubMed

Pers S, Gautschi M, Nuoffer J, Schwarz H, Christ E. Integration of adult patients with phenylketonuria into professional life: long-term follow-up of 27 patients in a single centre in Switzerland. Swiss Med Wkly. 2014;(December):1–6 http://doi.emh.ch/smw.2014.14074.

Burgard P, Ullrich K, Ballhausen D, Hennermann JB, Hollak CEM, Langeveld M, et al. Issues with European guidelines for phenylketonuria. Lancet Diabetes Endocrinol. 2017;5(9):681–3.PubMed

Jahja R, van Spronsen FJ, de Sonneville LMJ, van der Meere JJ, Bosch AM, Hollak CEM, et al. Long-term follow-up of cognition and mental health in adult phenylketonuria: a PKU-COBESO study. Behav Genet. 2017;47(5):486–97.PubMedPubMedCentral

Romani C, Palermo L, MacDonald A, Limback E, Hall SK, Geberhiwot T. The impact of phenylalanine levels on cognitive outcomes in adults with phenylketonuria: effects across tasks and developmental stages. Neuropsychology. 2017;31(3):242–54 http://www.ncbi.nlm.nih.gov/pubmed/28240926.PubMedPubMedCentral

Hofman DL, Champ CL, Lawton CL, Henderson M, Dye L. A systematic review of cognitive functioning in early treated adults with phenylketonuria. Orphanet J Rare Dis. 2018;13(1):150 http://www.ncbi.nlm.nih.gov/pubmed/30165883.PubMedPubMedCentral

Welsh MC, Pennington BF, Ozonoff S, Rouse B, McCabe ERB. Neuropsychology of early-treated phenylketonuria: specific executive function deficits. Child Dev. 1990;61(6):1697 https://www.jstor.org/stable/1130832?origin=crossref.PubMed

Brumm VL, Azen C, Moats RA, Stern AM, Broomand C, Nelson MD, et al. Neuropsychological outcome of subjects participating in the PKU adult collaborative study: a preliminary review. J Inherit Metab Dis. 2004;27(5):549–66.PubMed

Bodner KE, Aldridge K, Moffitt AJ, Peck D, White DA, Christ SE. A volumetric study of basal ganglia structures in individuals with early-treated phenylketonuria. Mol Genet Metab. 2012;107(3):302–7.PubMed

10.

Christ SE, Moffitt AJ, Peck D, White DA, Hilgard J. Decreased functional brain connectivity in individuals with early-treated phenylketonuria: evidence from resting state fMRI. J Inherit Metab Dis. 2012;35(5):807–16.PubMed

11.

Sundermann B, Pfleiderer B, Möller HE, Schwindt W, Weglage J, Lepsien J, et al. Tackling frontal lobe–related functions in PKU through functional brain imaging: a Stroop task in adult patients. J Inherit Metab Dis. 2011;34(3):711–21 http://link.springer.com/10.1007/s10545-011-9318-4.PubMed

12.

Van Spronsen FJ, Huijbregts SCJ, Bosch AM, Leuzzi V. Cognitive, neurophysiological, neurological and psychosocial outcomes in early-treated PKU-patients: a start toward standardized outcome measurement across development. Mol Genet Metab. 2011;104(SUPPL):S45–51. https://doi.org/10.1016/j.ymgme.2011.09.036.CrossRefPubMed

13.

Palermo L, Geberhiwot T, MacDonald A, Limback E, Hall SK, Romani C. Cognitive outcomes in early-treated adults with phenylketonuria (PKU): a comprehensive picture across domains. Neuropsychology. 2017;31(3):255–67 http://www.ncbi.nlm.nih.gov/pubmed/28080075.PubMedPubMedCentral

14.

Waisbren SE, Noel K, Fahrbach K, Cella C, Frame D, Dorenbaum A, et al. Phenylalanine blood levels and clinical outcomes in phenylketonuria: A systematic literature review and meta-analysis. Mol Genet Metab. 2007;92(1–2):63–70.PubMed

15.

Christ SE, Huijbregts SCJ, de Sonneville LMJ, White DA. Executive function in early-treated phenylketonuria: Profile and underlying mechanisms. Mol Genet Metab. 2009;99(SUPPL):S22–32. https://doi.org/10.1016/j.ymgme.2009.10.007.CrossRef

16.

Bik-Multanowski Miroslaw M, Pietrzyk JJ, Mozrzymas R. Routine use of CANTAB system for detection of neuropsychological deficits in patients with PKU. Mol Genet Metab. 2011;102(2):210–3. https://doi.org/10.1016/j.ymgme.2010.10.003.CrossRefPubMed

17.

Baddeley A. Working memory. Science. 1992;255(5044):556–9.

18.

Kane MJ, Brown LH, McVay JC, Silvia PJ, Myin-germeys I, Kwapil TR. For whom the mind wanders, and when executive control in daily life. Psychol Sci. 2007;18(7):614–21 http://journals.sagepub.com/doi/pdf/10.1111/j.1467-9280.2007.01948.x.PubMed

19.

Christ SE, Price MH, Bodner KE, Saville C, Moffitt AJ, Peck D. Morphometric analysis of gray matter integrity in individuals with early-treated phenylketonuria. Mol Genet Metab. 2016;118(1):3–8.PubMed

20.

Dezortová M, Hájek M, Tintěra J, Hejcmanová L, Syková E. MR in phenylketonuria-related brain lesions. Acta Radiol. 2001;42(5):459–66.PubMed

21.

Bik-Multanowski M, Didycz B, Mozrzymas R, Nowacka M, Kaluzny L, Cichy W, et al. Quality of life in noncompliant adults with phenylketonuria after resumption of the diet. J Inherit Metab Dis. 2008;31(S2):415–8 Available from: http://www.ncbi.nlm.nih.gov/pubmed/18956249.

22.

Anderson PJ, Leuzzi V. White matter pathology in phenylketonuria. Mol Genet Metab. 2009;99(SUPPL):S3–9. https://doi.org/10.1016/j.ymgme.2009.10.005.CrossRef

23.

Pérez-Dueñas B, Pujol J, Soriano-Mas C, Ortiz H, Artuch R, Vilaseca MA, et al. Global and regional volume changes in the brains of patients with phenylketonuria. Neurol Int. 2006;66(7):1074–8 http://www.scopus.com/inward/record.url?eid=2-s2.0-33646115442&partnerID=40&md5=1c59bdc45e736438aacef75e827b5179.

24.

Christ SE, Moffitt AJ, Peck D, White DA. The effects of tetrahydrobiopterin (BH4) treatment on brain function in individuals with phenylketonuria. NeuroImage Clin. 2013;3:539–47.PubMedPubMedCentral

25.

Christ SE, Moffitt AJ, Peck D. Disruption of prefrontal function and connectivity in individuals with phenylketonuria. Mol Genet Metab. 2010;99(SUPPL):S33–40. https://doi.org/10.1016/j.ymgme.2009.09.014.CrossRefPubMed

26.

Leuzzi V, Bianchi MC, Tosetti M, Carducci CL, Carducci CA, Antonozzi I. Clinical significance of brain phenylalanine concentration assessed by in vivo proton magnetic resonance spectroscopy in phenylketonuria. J Inherit Metab Dis. 2000;23(6):563–70 http://www.ncbi.nlm.nih.gov/pubmed/11032331.PubMed

27.

Channon S, Goodman G, Zlotowitz S, Mockler C, Lee PJ. Effects of dietary management of phenylketonuria on long-term cognitive outcome. Arch Dis Child. 2007;292(3):213–8 http://www.ncbi.nlm.nih.gov/pubmed/17068073.

28.

ten Hoedt AE, de Sonneville LMJ, Francois B, ter Horst NM, Janssen MCH, Estela Rubio-Gozalbo M, et al. High phenylalanine levels directly affect mood and sustained attention in adults with phenylketonuria: a randomised, double-blind, placebo-controlled, crossover trial. J Inherit Metab Dis. 2010;34:165–71 www.childrensmemorial.org/.PubMedPubMedCentral

29.

van Wegberg AMJ, MacDonald A, Ahring K, Bélanger-Quintana A, Blau N, Bosch AM, et al. The complete European guidelines on phenylketonuria: diagnosis and treatment. Orphanet J Rare Dis. 2017;12(1):162 http://www.ncbi.nlm.nih.gov/pubmed/29025426.PubMedPubMedCentral

30.

Brown CS, Lichter-Konecki U. Phenylketonuria (PKU): a problem solved? Mol Genet Metab Reports. 2016;6:8–12. https://doi.org/10.1016/j.ymgmr.2015.12.004.CrossRef

31.

Burton BK, Leviton L. Reaching out to the lost generation of adults with early-treated phenylketonuria (PKU). Mol Genet Metab. 2010;101(2–3):146–8.PubMed

32.

Chan A, Tetzlaff JM, Gøtzsche PC, Altman DG, Mann H, Berlin JA, et al. SPIRIT 2013 explanation and elaboration: guidance for protocols of clinical trials. BMJ. 2013;346:e7586.PubMedPubMedCentral

33.

Guigoz Epalinges Y. Dietary proteins in humans: basic aspects and consumption in Switzerland. Int J Vitam Nutr Res. 2011;81(3):87–100.

34.

Burns TS, Stargel WW, Hurwitz A. Bioavailability of phenylalanine and aspartate from aspartame (20 mg/kg) in capsules and solution. Metabolism. 1990;39(11):1200–3 https://www.sciencedirect.com/science/article/pii/002604959090095T.PubMed

35.

MacLeod EL, Gleason ST, van Calcar SC, Ney DM. Reassessment of phenylalanine tolerance in adults with phenylketonuria is needed as body mass changes. Mol Genet Metab. 2009;98(4):331–7.PubMedPubMedCentral

36.

Kaufman S. A model of human phenylalanine metabolism in normal subjects and in phenylketonuric patients. Med Sci. 1999;96:3160–4.

37.

Zimmermann P, Fimm B. Testbatterie zur Aufmerksamkeitsprüfung. Würselen: Psytest; 2009.

38.

Wechsler D. Wechsler adult intelligence scale - fourth edition (WAIS-IV). 22nd ed. San Antonio: NCS Pearson; 2008. p. 498.

39.

Delis DC, Kaplan E, Kramer JH. D-KEFS: examiners manual. San Antonio: The Psychological Corporation; 2001.

40.

Tiffin J, Asher EJ. The Purdue Pegboard: norms and studies of reliability and validity. J Appl Psychol. 1948;32(3):234–47.PubMed

41.

Albani C, Blaser G, Geyer M, Schmutzer G, Brähler E, Bailer H, et al. Überprüfung der Gütekriterien der deutschen Kurzform des Fragebogens Profile of Mood States (POMS) in einer repräsentativen Bevölkerungsstichprobe. Psychother Psychosom Med Psychol. 2005;55(7):324–30.PubMed

42.

Dozois DJA, Dobson KS, Ahnberg JL. A psychometric evaluation of the Beck Depression Inventory-II. Psychol Assess. 1998;10(2):83–9.

43.

Regnault A, Burlina A, Cunningham A, Bettiol E, Moreau-Stucker F. Development and psychometric validation of measures to assess the impact of phenylketonuria and its dietary treatment on patients ’ and parents ’ quality of life : the phenylketonuria – quality of life (PKU-QOL) questionnaires. Orphanet J Rare Dis. 2015;10(1):59.PubMedPubMedCentral

44.

Fujiyoshi K, Hikishima K, Nakahara J, Tsuji O, Hata J, Konomi T, et al. Application of q-space diffusion MRI for the visualization of white matter. J Neurosci. 2016;36(9):2796–808 http://www.jneurosci.org/cgi/doi/10.1523/JNEUROSCI.1770-15.2016.PubMedPubMedCentral

45.

Öz G, Tkáč I. Short-echo, single-shot, full-intensity proton magnetic resonance spectroscopy for neurochemical profiling at 4 T: validation in the cerebellum and brainstem. Magn Reson Med. 2011;65(4):901–10 http://www.ncbi.nlm.nih.gov/pubmed/21413056.PubMed

46.

Jacola LM, Willard VW, Ashford JM, Ogg RJ, Scoggins MA, Jones MM, et al. Clinical utility of the N-back task in functional neuroimaging studies of working memory. J Clin Exp Neuropsychol. 2014;36(8):875–86.PubMedPubMedCentral

47.

Kreis R, Zwygart K, Boesch C, Nuoffer J-M. Reproducibility of cerebral phenylalanine levels in patients with phenylketonuria determined by ¹ H-MR spectroscopy. Magn Reson Med. 2009;62(1):11–6 http://doi.wiley.com/10.1002/mrm.21983.PubMed

48.

Piaggio G, Elbourne DR, Pocock SJ, Evans SJW, Altman DG, CONSORT Group. Reporting of noninferiority and equivalence randomized trials. JAMA. 2012;308(24):2594 http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2012.87802.PubMed

49.

Feillet F, Agostoni C. Nutritional issues in treating phenylketonuria. J Inherit Metab Dis. 2010;33(6):659–64.PubMed

50.

Bilder DA, Kobori JA, Cohen-Pfeffer JL, Johnson EM, Jurecki ER, Grant ML. Neuropsychiatric comorbidities in adults with phenylketonuria: a retrospective cohort study. Mol Genet Metab. 2017;121(1):1–8.PubMed

51.

Hollak CE, Lachmann R. (Eds.). Inherited Metabolic Disease in Adults: A Clinical Guide. Oxford University Press; 2016.

52.

Bilder DA, Noel JK, Baker ER, Irish W, Chen Y, Merilainen MJ, et al. systematic review and meta-analysis of neuropsychiatric symptoms and executive functioning in adults with phenylketonuria. Dev Neuropsychol. 2016;41(4):245–60. https://doi.org/10.1080/87565641.2016.1243109.CrossRefPubMedPubMedCentral

53.

Schmidt E, Rupp A, Burgard P, Pietz J, Weglage J, de Sonneville L. Sustained attention in adult phenylketonuria: the influence of the concurrent phenylalanine-blood-level*. J Clin Exp Neuropsychol. 1994;16(5):681–8.PubMed

54.

FDA. FDA approves new treatment for a rare genetic disorder, Fabry disease. 2018; https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm608835.htm. Cited 28 Sept 2018.

55.

EMEA. EMEA-001951-PIP01–16 | European Medicines Agency. 2018. https://www.ema.europa.eu/medicines/human/paediatric-investigation-plans/emea-001951-pip01-16. Accessed 28 Sept 2018.

56.

Levy HL, Sarkissian CN, Scriver CR. Phenylalanine ammonia lyase (PAL): From discovery to enzyme substitution therapy for phenylketonuria. Mol Genet Metab. 2018;124(4):223–9 https://linkinghub.elsevier.com/retrieve/pii/S1096719218302920.PubMed

57.

Jiang J, Amato RS, Weng HH, Burton BK, Stuy M, Longo N, et al. Pegvaliase for the treatment of phenylketonuria: a pivotal, double-blind randomized discontinuation Phase 3 clinical trial. Mol Genet Metab. 2018;24(1):20–6. https://doi.org/10.1016/j.ymgme.2018.03.003.CrossRef

58.

Thomas J, Levy H, Amato S, Vockley J, Zori R, Dimmock D, et al. Pegvaliase for the treatment of phenylketonuria: Results of a long-term phase 3 clinical trial program (PRISM). Mol Genet Metab. 2018;124:1096–7192 http://creativecommons.org/licenses/BY/4.0/.

Title: Impact of phenylalanine on cognitive, cerebral, and neurometabolic parameters in adult patients with phenylketonuria (the PICO study): a randomized, placebo-controlled, crossover, noninferiority trial
Authors: Roman Trepp
Raphaela Muri
Stephanie Abgottspon
Lenka Bosanska
Michel Hochuli
Johannes Slotboom
Christian Rummel
Roland Kreis
Regula Everts
Publication date: 01-12-2020
Publisher: BioMed Central
Keyword: Phenylketonuria
Published in: Trials / Issue 1/2020
Electronic ISSN: 1745-6215
DOI: https://doi.org/10.1186/s13063-019-4022-z

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Impact of phenylalanine on cognitive, cerebral, and neurometabolic parameters in adult patients with phenylketonuria (the PICO study): a randomized, placebo-controlled, crossover, noninferiority trial

Abstract

Background

Methods

Participants

Objectives

Randomization

Discussion

Trial registration

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Abstract

Background

Methods

Participants

Objectives

Randomization

Discussion

Trial registration

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